Pere Domingo

Dual treatment with lopinavir–ritonavir plus lamivudine versus triple treatment with lopinavir–ritonavir plus lamivudine or emtricitabine and a second nucleos(t)ide reverse transcriptase inhibitor for maintenance of HIV-1 viral suppression (OLE): a randomised, open-label, non-inferiority trial

BACKGROUNDnOur objective was to assess therapeutic non-inferiority of dual treatment with lopinavir-ritonavir and lamivudine to triple treatment with lopinavir-ritonavir plus two nucleos(t)ides for maintenance of HIV-1 viral suppression.nnnMETHODSnIn this randomised, open-label, non-inferiority trial, we recruited patients from 32 HIV units in hospitals in Spain and France. Eligible patients were HIV-infected adults (aged ≥18 years) with HIV-1 RNA of less than 50 copies per mL, for at least 6 months on triple treatment with lopinavir-ritonavir (twice daily) plus lamivudine or emtricitabine and a second nucleos(t)ide, with no resistance or virological failure to these drugs, and no positive hepatitis B serum surface antigen. Investigators at each centre randomly assigned patients (1:1; block size of four; stratified by time to suppression [<1 year or >1 year] and nadir CD4 cell count [<100 cells per μL or >100 cells per μL]; computer-generated random sequence) to continue triple treatment or switch to dual treatment (oral lopinavir 400 mg and oral ritonavir 100 mg twice daily plus oral lamivudine 300 mg once daily). The primary endpoint was response to treatment in the intention-to-treat population (all randomised patients) at 48 weeks. The non-inferiority margin was 12%. This study is registered with ClinicalTrials.gov, number NCT01471821.nnnFINDINGSnBetween Oct 1, 2011, and April 1, 2013, we randomly assigned 250 participants to continue triple treatment (127 [51%] patients) or switch to dual treatment (123 [49%] patients). In the intention-to-treat population, 110 (86·6%) of 127 patients in the triple-treatment group responded to treatment versus 108 (87·8%) of 123 in the dual-treatment group (difference -1·2% [95% CI -9·6 to 7·3]; p=0·92), meeting the criteria for non-inferiority. Serious adverse events occurred in eight (7%) patients in the triple-treatment group and five (4%) in the dual-treatment group (p=0·515), and study drug discontinuations due to adverse events occurred in four (3%) in the triple-treatment group and one (1%) in the dual-treatment group (p=0·223).nnnINTERPRETATIONnDual treatment with lopinavir-ritonavir plus lamivudine has non-inferior therapeutic efficacy and is similarly tolerated to triple treatment.nnnFUNDINGnAbbVie and Red Temática Cooperativa de Investigación en Sida.

Discontinuation of Primary and Secondary Toxoplasma gondii Prophylaxis Is Safe in HIV-Infected Patients after Immunological Restoration with Highly Active Antiretroviral Therapy: Results of an Open, Randomized, Multicenter Clinical Trial

BACKGROUNDnTo our knowledge, no randomized trials have evaluated whether prophylaxis against toxoplasmic encephalitis can be safely discontinued after the CD4+ T cell count increases in response to highly active antiretroviral therapy.nnnMETHODSnWe conducted a randomized, nonblinded, multicenter clinical trial of the discontinuation of primary or secondary prophylaxis against toxoplasmic encephalitis in human immunodeficiency virus (HIV)-infected patients with a sustained response to antiretroviral therapy (defined as a CD4+ T cell count of > or =200 cells/mm3 and a plasma HIV type 1 [HIV-1] RNA level of <5000 copies/mL for at least 3 months). Prophylaxis was restarted if the CD4+ T cell count decreased to <200 cells/mm3.nnnRESULTSnThe 381 patients receiving primary prophylaxis had a median CD4+ T cell count on study entry of 343 cells/mm3, and 318 (83%) of 381 patients had undetectable HIV-1 RNA in plasma. After a median follow-up period of 25 months (409 person-years), there were no episodes of toxoplasmic encephalitis among the 196 patients who discontinued prophylaxis (at 1 year, the upper limit of the 95% confidence interval for relapse rate was 2.40%). For the 57 patients receiving secondary prophylaxis, the median CD4+ T cell count on entry was 407 cells/mm3, and 49 (86%) of 57 patients had undetectable HIV-1 RNA in plasma. After a median follow-up period of 30.5 months (69 person-years), there were no episodes of toxoplasmic encephalitis among the 28 patients who discontinued prophylaxis (at 1 year, the upper limit of the 95% confidence interval for relapse rate was 16%).nnnCONCLUSIONSnIn HIV-infected adult patients receiving effective highly active antiretroviral therapy, primary and secondary prophylaxis against toxoplasmic encephalitis can be safely discontinued after the CD4+ T cell count has increased to > or =200 cells/mm3 for >3 months.

Differences between HIV‐infected and uninfected adults in the contributions of smoking, diabetes and hypertension to acute coronary syndrome: two parallel case–control studies

The aim of the study was to assess the separate contributions of smoking, diabetes and hypertension to acute coronary syndrome (ACS) in HIV‐infected adults relative to uninfected adults.

Improvement of Mitochondrial Toxicity in Patients receiving a Nucleoside Reverse-Transcriptase Inhibitor-Sparing Strategy: Results from the Multicenter Study with Nevirapine and Kaletra (MULTINEKA)

BACKGROUNDnNucleoside reverse-transcriptase inhibitor (NRTI)-related mitochondrial toxicity has been suggested as a key factor in the induction of antiretroviral-related lipoatrophy. This study aimed to evaluate in vivo the effects of NRTI withdrawal on mitochondrial parameters and body fat distribution.nnnMETHODSnA multicenter, prospective, randomized trial assessed the efficacy and tolerability of switching to lopinavir-ritonavir plus nevirapine (nevirapine group; n = 34), compared with lopinavir-ritonavir plus 2 NRTIs (control group; n = 33) in a group of human immunodeficiency virus-infected adults with virological suppression. A subset of 35 individuals (20 from the nevirapine group and 15 from the control group) were evaluated for changes in the mitochondrial DNA (mtDNA) to nuclear DNA ratio and cytochrome c oxidase (COX) activity after NRTI withdrawal. Dual-energy X-ray absorptiometry (DEXA) scans were used to objectively quantify fat redistribution over time.nnnRESULTSnThe nevirapine group experienced a progressive increase in mtDNA content (a 40% increase at week 48; P = .039 for comparison between groups) and in the COX activity (26% and 32% at weeks 24 and 48, respectively; P = .01 and P = .09 for comparison between groups, respectively). There were no statistically significant between-group differences in DEXA scans at week 48, although a higher fat increase in extremities was observed in the nevirapine group. No virologic failures occurred in either treatment arm.nnnCONCLUSIONSnSwitching to a nucleoside-sparing regimen of nevirapine and lopinavir-ritonavir maintained full antiviral efficacy and led to an improvement in mitochondrial parameters, which suggests a reversion of nucleoside-associated mitochondrial toxicity. Although DEXA scans performed during the study only revealed slight changes in fat redistribution, a longer follow-up period may show a positive correlation between reduced mitochondrial toxicity and a clinical improvement of lipodystrophy.

Lipid profiles for nevirapine vs. atazanavir/ritonavir, both combined with tenofovir disoproxil fumarate and emtricitabine over 48 weeks, in treatment-naïve HIV-1-infected patients (the ARTEN study).

Dyslipidaemic effects of antiretrovirals (ARVs) may contribute to increased cardiovascular risk (CR) in HIV‐1‐infected patients. The ARTEN (atazanavir/ritonavir on a background of tenofovir and emtricitabine vs. nevirapine on the same background, in naïve HIV‐1‐infected patients) study compared prospectively ritonavir‐boosted atazanavir (ATZ/r) 300u2003mg/100u2003mg once daily (qd) with immediate release nevirapine (NVP) 200u2003mg twice daily or 400u2003mg qd, each combined with fixed‐dose tenofovir 300u2003mg/emtricitabine 200u2003mg qd in 569 ARV‐naïve HIV‐1‐infected patients. Lipid profiles and CR from baseline to week 48 are reported.

Different Plasma Markers of Inflammation Are Influenced by Immune Recovery and cART Composition or Intensification in Treated HIV Infected Individuals

Background HIV-1 infection increases plasma levels of inflammatory markers. Combination antiretroviral therapy (cART) does not restore inflammatory markers to normal levels. Since intensification of cART with raltegravir reduced CD8 T-cell activation in the Discor-Ral and IntegRal studies, we have evaluated the effect of raltegravir intensification on several soluble inflammation markers in these studies. Methods Longitudinal plasma samples (0–48 weeks) from the IntegRal (nu200a=u200a67, 22 control and 45 intensified individuals) and the Discor-Ral studies (44 individuals with CD4 T-cell counts<350 cells/µl, 14 control and 30 intensified) were assayed for 25 markers. Mann-Whitney, Wilcoxon, Spearman test and linear mixed models were used for analysis. Results At baseline, different inflammatory markers were strongly associated with HCV co-infection, lower CD4 counts and with cART regimens (being higher in PI-treated individuals), but poorly correlated with detection of markers of residual viral replication. Although raltegravir intensification reduced inflammation in individuals with lower CD4 T-cell counts, no effect of intensification was observed on plasma markers of inflammation in a global analysis. An association was found, however, between reductions in immune activation and plasma levels of the coagulation marker D-dimer, which exclusively decreased in intensified patients on protease inhibitor (PI)-based cART regimens (Pu200a=u200a0.040). Conclusions The inflammatory profile in treated HIV-infected individuals showed a complex association with HCV co-infection, the levels of CD4 T cells and the cART regimen. Raltegravir intensification specifically reduced D-dimer levels in PI-treated patients, highlighting the link between cART composition and residual viral replication; however, raltegravir had little effect on other inflammatory markers.

Late Initiation of HAART Among HIV-Infected Patients in Spain Is Frequent and Related to a Higher Rate of Virological Failure but not to Immigrant Status

Abstract Purpose: To determine whether immigrant status is associated with late initiation of highly active antiretroviral treatment (HAART) and/or poor response to antiretrovirals. Methods: GESIDA 5808 is a multicenter, retrospective cohort study (inclusion period January 2005 through December 2006) of treatment-naïve patients initiating HAART that compares HIV-infected patients who are immigrants with Spanish-born patients. A late starter (LS) was defined as any patient starting HAART with a CD4+ lymphocyte count <200 cells/μL and/or diagnosis of an AIDS-defining illness before or at the start of therapy. The primary endpoint was time to treatment failure (TTF), defined as virological failure (VF), death, opportunistic infection, treatment discontinuation/switch (D/S), or missing patient. Secondary endpoints were time to treatment failure as observed data (TTO; censoring missing patients) and time to virological failure (TVF; censoring missing patients and D/S not due to VF). Results: LS accounted for 56% of the patients. Lower educational and socioeconomic level and intravenous drug use (IVDU) were associated with categorization as LS, but immigrant status was not. Cox regression analysis (hazard ratio [HR]; 95% CI) between LS and non-LS patients showed no differences in TTF (0.97; 0.78–1.20) or TTO (1.18; 0.88–1.58), although it did reveal a difference in TVF (1.97; 1.18–3.29). CD4+ lymphocyte recovery was equivalent for both LS and non-LS patients (159 vs 173). Conclusions: In our cohort, immigrant status was not shown to be related to late initiation of HAART. Although LS patients did not have a longer TTF for any reason, TVF was significantly shorter. Despite universal free access to HAART in Spain, measures to ensure early diagnosis and treatment of HIV infection are necessary.

Contribution of genetic background and antiretroviral therapy to body fat changes in antiretroviral-naive HIV-infected adults

OBJECTIVESnTo evaluate the association of host genetics with changes in limb or trunk fat in a group of antiretroviral therapy (ART)-naive HIV-infected patients prospectively followed up according to the initiation and the type of ART.nnnMETHODSnFifty single nucleotide polymorphisms (SNPs) in 26 genes, associated with obesity, insulin resistance, lipid metabolism or lipodystrophy in previously published genetic studies, were assessed in ART-naive HIV-infected Caucasian patients divided into three groups: 24 (27%) did not start ART, 29 (32.6%) received zidovudine or stavudine and 36 (40.4%) received neither zidovudine nor stavudine in their initial regimen. Patients underwent body fat measurements (using dual-energy X-ray absorptiometry) at baseline and Month 12. A multivariate model using backward stepwise elimination was used to assess the influence of SNPs and baseline levels of non-genetic covariates on changes in limb or trunk fat.nnnRESULTSnThe baseline characteristics were: 73% men, 17% coinfected with hepatitis C virus and/or hepatitis B virus, median age 37 years, median CD4+ T cell count 228/mm(3), median HIV-RNA 5.2 log copies/mL, median plasma glucose 85 mg/dL, median plasma insulin 9.1 IU/mL, median limb fat 5.6 kg and median trunk fat 7.0 kg. There were no baseline differences among the three groups except for the CD4+ T cell count. The decrease in limb fat was greater in the no-ART group relative to the other two groups (Pu200a<u200a0.05). The multivariate model showed associations of rs1801278 in IRS1 (Pu200a=u200a0.029, ORu200a=u200a0.13), baseline viral load (Pu200a=u200a0.006; ORu200a=u200a4.453) and baseline glucose levels (Pu200a=u200a0.008, ORu200a=u200a0.926) with loss of limb fat, and rs2228671 in LDLR (Pu200a=u200a0.012, ORu200a=u200a0.108), rs405509 in APOE (Pu200a=u200a0.048, ORu200a=u200a0.205), baseline viral load (Pu200a=u200a0.005, ORu200a=u200a0.186) and baseline CD4+ T cell count (Pu200a=u200a0.01, ORu200a=u200a1.008) with gain of trunk fat.nnnCONCLUSIONSnSpecific polymorphisms in IRS1 (limb fat loss) and LDLR and APOE (trunk fat gain) were identified as independent markers of fat changes irrespective of the initiation of ART and the type of ART and deserve further validation.

Inmunoterapia y vacunas terapéuticas en la infección por VIH

El desarrollo de resistencia a la medicacion, la aparicion de efectos adversos a medio y a largo plazo y el elevado coste economico constituyen importantes limitaciones para el cumplimiento de por vida del tratamiento antirretroviral de gran actividad (TARGA). Se ha propuesto la combinacion de TARGA con inmunoterapias para restaurar y/o potenciar las respuestas inmunoespecificas frente al VIH, con el ultimo proposito de controlar la replicacion viral en ausencia de TARGA durante periodos prolongados de tiempo. Los defectos funcionales de las respuestas celulares y humorales, asi como la interrelacion entre ellas explicarian la falta de control por parte del sistema inmunologico de la replicacion viral. Se han investigado distintos tipos de terapias inmunomediadas para solucionar los problemas antes mencionados, entre ellas la inmunoterapia pasiva, la utilizacion de citocinas, las interrupciones estructuradas de tratamiento, la utilizacion de inmunosupresores y las vacunas terapeuticas. Los todavia limitados conocimientos de que se dispone acerca de los mecanismos inmunologicos capaces de controlar la replicacion viral del VIH y de las causas del deterioro de la inmunidad celular y humoral han producido modestos beneficios de las terapias inmunomedidas obtenidos hasta la actualidad, y en una escasa o ninguna aplicabilidad en la practica clinica diaria, quedando, hoy por hoy, confinados al campo de la investigacion. La disponibilidad de una optima vacuna terapeutica seria un gran avance cientifico, comparable a la llegada de los inhibidores de la proteasa a la practica clinica, por lo que actualmente debe ser una linea prioritaria de investigacion.

Immunotherapy and therapeutic vaccines in HIV infection

Resistance to medication, adverse effects in the medium-long term, and cost are important limitations to lifelong adherence to highly active antiretroviral therapy (HAART). The combination of HAART with immune therapy to restore and/or boost immune-specific responses to HIV has been proposed, with the ultimate aim of controlling viral replication in the absence of HAART over long periods. The functional defects of the cellular and humoral responses would explain the lack of control of the immune system over viral replication. Different types of immune-mediated therapy have been investigated to solve these problems, including passive immune therapy, cytokines, structured treatment interruptions, immunosuppressors and therapeutic vaccines. Our still limited knowledge of immune mechanisms which can control HIV viral replication and of the causes of the deterioration of cellular and humoral immunity have produced only modest benefits in immune-mediated therapy, and are therefore confined to research for the time being. The availability of an optimal therapeutic vaccine would be an important scientific advance which could be compared with the arrival of protease inhibitors in clinical practice. Therefore, priority should be given to research in this field.